1. Th1 cytokines TNF-α and IFN-γ promote corticosteroid resistance in developing human airway smooth muscle.
- Author
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Britt Jr., Rodney D., Thompson, Michael A., Sasse, Sarah, Pabelick, Christina M., Gerber, Anthony N., and Prakash, Y. S.
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ASTHMA treatment , *ASTHMA -- Immunological aspects , *CYTOKINES , *TUMOR necrosis factors , *CORTICOSTEROIDS , *AIRWAY (Anatomy) , *SMOOTH muscle physiology - Abstract
Corticosteroids (CSs) are commonly used to manage wheezing and asthma in pediatric populations. Although corticosteroids are effective in alleviating airway diseases, some children with more moderate-severe asthma phenotypes show CS resistance and exhibit significant airflow obstruction, persistent inflammation, and more frequent exacerbations. Previous studies have demonstrated that Th1 cytokines, such as TNF-γ and IFN-γ, promote CS resistance in adult human airway smooth muscle (ASM). In the present study, using a human fetal ASM cell model, we tested the hypothesis that TNF-γ/IFN-γ induces CS resistance. In contrast to TNF-β or IFN-γ alone, the combination of TNF-β/IFN-γ blunted the ability of fluticasone propionate (FP) to reduce expression of the chemokines CCL5 and CXCL10 despite expression of key anti-inflammatory glucocorticoid receptor target genes being largely unaffected by TNF-β/IFN-γ. Expression of the NF-B subunit p65 and phosphorylation of Stat1 were elevated in cells treated with TNF-β/IFN-γ, an effect that remained in the presence of FP. siRNA knockdown studies demonstrated the effects of TNF-β/IFN-γ on increased p65 are mediated by Stat1, a transcription factor activated by IFN-γ. Expression of TNFAIP3, a negative regulator of NF-B activity, was not altered by TNF-β/IFN-γ. However, the effects of TNF-β/IFN-γ were partially reduced by overexpression of TNFAIP3 but did not influence p65 expression. Together, these data suggest that IFN-γ augments the effects of TNF-β on chemokines by enhancing expression of key inflammatory pathways in the presence of CS. Interactions between TNF-β- and IFN-γ-mediated pathways may promote inflammation in asthmatic children resistant to CSs. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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